Project Summary/Abstract Obesity is major modifiable risk factor for cardiometabolic disease that disproportionally affects women. Current behavioral weight loss interventions produce only modest weight loss with a high rate of recidivism, and are less likely to be successful in women. Evolutionary considerations can help integrate separate lines of research on how reproductive and metabolic physiology are related, and provide important insight into the pathophysiology of obesity in women. Gonadotropins and ovarian hormones are considered key regulators of energy homeostasis and body composition among women, and suppression impacts energy intake and expenditure in ways that could inhibit weight loss. Recently, a unique functional dysregulation of the hypothalamic pituitary ovarian (HPO) axis has been observed in regularly cycling (eumennorheic) women with obesity, resulting in lower levels of gonadotropins and ovarian hormones compared to normal weight women. This dysregulation may be highly prevalent and is associated with cardiometabolic risk factors and subfertility. While it has been presumed that this disorder improves with weight loss, gonadotropins and ovarian hormones are suppressed in normal weight women response to energy restriction. This suppression reflects an adaptive response to strategically shift energy away from reproduction and toward survival during resource scarcity. Therefore, restricting energy through behavioral weight loss may prolong or induce HPO axis dysregulation in some women, which may in turn inhibit weight loss. The proposed research seeks to fill gaps in knowledge regarding the prevalence and etiology of obesity-related HPO axis dysregulation (Aim 1), examine the extent to which it improves with a behavioral weight loss intervention (Aim 2), and explore the impact of this disorder on energy intake and expenditure (including physical activity and sedentary behavior), and weight loss (Aim 3). The study design is a prospective, longitudinal, observational study of 40 eumemorhheic, pre-menopausal, obese women enrolled in a NIH-funded 1-year randomized weight loss trial. Participants will undergo measures of HPO axis function over complete menstrual cycles the month prior to and the first 3 months of the behavioral weight loss intervention. Dr. Caldwell will perform these measures and those that complement them obtained in the parent trial (changes in weight, body composition, cardiometabolic parameters, energy intake, and energy expenditure). The central premise is that a less metabolically healthy obese state is associated with a greater degree of HPO axis dysregulation; that reducing energy availability during behavioral weight loss will prolong or induce HPO axis dysregulation in some women; and that the persistence or development of HPO axis dysregulation will inhibit weight loss and promote weight gain. Dr. Caldwell will gain substantive career development training through conducting this research and form critical research collaborations that support her distinctive line of research. She will leverage these findings to transition to a highly impactful independent research career developing novel approaches to reduce obesity by the conclusion of the K01 award period. !